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Objective: The objective of this study was to determine the ability of the surgeon to distinguish between deep and superficial myometrial invasion on gross inspection as compared to frozen section. Methods: All patients undergoing hysterectomy for endometrial cancer were eligible for this prospective study carried out at a single institution. After removal of the uterus, the specimen was bi-valved and the depth of myometrial invasion was determined grossly by the attending surgeon (gross). The depth of myometrial invasion by visible tumor was measured in millimeters and then described as “superficial” or “deep” if the invasion did not or did extend into the outer half of the myometrial thickness, respectively. The specimen was sent for frozen section evaluation of tumor grade and depth of invasion (frozen). We calculated the sensitivity of each method, gross and frozen, to correctly identify deep myometrial invasion, the specificity to correctly identify superficial or no invasion, and the accuracy, defined as the number of true positives plus true negatives divided by the total number of cases. The final pathologic assessment of myometrial invasion (final) was considered the gold standard for comparison. Results: Between 4/4/2011 and 4/9/2014, a total of 220 patients underwent hysterectomy by the division of gynecologic oncology in the San Diego area of Kaiser Permanente for a preoperative diagnosis of endometrial cancer. Of these, 196 had complete specimen information (gross, frozen, and final). On final, 35 specimens had deep invasion (17.9%). The sensitivity of gross to detect deep invasion was 54.3% and 77.1% for frozen. Specificity for gross and frozen was 93.8% and 98.8%, respectively. Gross inspection failed to identify deep myometrial invasion in 16 (45.7%) of the cases, frozen failed to identify deep myometrial invasion in 8 (22.9%) of the cases, and both gross and frozen failed to identify deep myometrial invasion in 7 (20.0%) of the cases. Conclusions: Frozen section demonstrates greater accuracy and sensitivity in the intraoperative determination of deep myometrial invasion. This should be considered if intraoperative assessment is used to determine staging or treatment decisions.

Purpose The purpose of the study was to determine if a diagnosis of ovarian cancer is independently associated with an increased risk of Clostridium difficile infection (CDI).

Ovarian cancer spreads via cell shedding and growth within malignant ascites. Effective targeted therapies have not been developed for ovarian cancer. Ascites contains an abundance of matrix proteins, and spheroids maintain integrin receptor expression. Through databases analyses we find that elevated osteopontin (OPN), β5 integrin, and focal adhesion kinase (FAK) mRNA levels are associated with decreased overall survival of serous ovarian cancer patients treated with platinum and taxol. In ovarian tumor tissue arrays, increased FAK activation (FAK Y397 phosphorylation) correlated with elevated tumor grade in parallel with increased in β5 integin and OPN levels. FAK is a cytoplasmic tyrosine kinase that remains active in spheroids, and treatment of seven ovarian carcinoma cell lines with sub-micromolar levels of FAK inhibitor (PND-1186) identified sensitive (HEY and OVCAR8), intermediate (OVCAR3, ID8-IP, and IGROV1-IP), and resistant (SKOV3-IP and OVCAR10) cells to blockage of growth under anchorage-independent conditions. Genetic or pharmacological FAK inhibition within ID8-IP or HEY cells selectively prevents anchorage-independent growth in culture and tumor growth in mice with corresponding reductions in β5 integrin and OPN expression. β5 knockdown reduced HEY growth in soft agar, tumor growth in mice, FAK Y397 phosphorylation, and OPN expression in spheroids. Although FAK inhibitor resistant ovarian carcinoma cells (SKOV3-IP and OVCAR10) were associated with anchorage-independent Akt S473 phosphorylation, membrane-targeted and activated Akt expression in sensitive cells (HEY and OVCAR8) resulted in only a partial rescue of FAK inhibitor-associated growth block. These results support the hypothesis that OPN, αvβ5 integrins, and FAK may function as a signaling axis promoting ovarian tumor progression. Although Akt signaling pathway activation is a common event in serous ovarian cancer, our results suggest that this may not impart complete resistance to FAK inhibitor treatment. Supported by NIH CA102310 Citation Format: Isabelle Tancioni, Sean Uryu, Florian Sulzmaier, Nina Shah, Christine Lawson, Nichol L.G. Miller, Christine Jean, Xiao Lei Chen, Kristy K. Ward, David D. Schlaepfer. Genetic and pharmacological FAK inhibition disrupt a β5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 752. doi:10.1158/1538-7445.AM2014-752

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that undergoes gene amplification in >20% of serous ovarian cancers. In addition to increased tumor growth and spread, ovarian cancer patients with FAK amplification have a poorer prognosis with decreased overall survival. Merlin, a product of the NF2 tumor suppressor gene, is being evaluated as a biomarker for sensitivity to FAK inhibition in human clinical trials for malignant mesothelioma. As it remains undetermined whether linkages exist between merlin and FAK in other tumor types, we evaluated nine human and two murine ovarian cancer cell lines with sub-micromolar levels of FAK inhibitor (PF-271) for effects on anchorage-independent cell growth. Cells were identified as sensitive (OVCAR3, OVCAR8, HEY, ID8-IP), intermediate (A2780, IGROV1), or resistant (OVCAR10, IGROV1-IP, SKOV3, SKOV3-IP, 5009) to FAK inhibition. Notably, merlin protein levels were high in all resistant cell lines, moderate in intermediate cell lines, and low or undetectable in sensitive cell lines. Oral FAK inhibitor administration reduced orthotopic tumor growth of sensitive (ID8-IP, low merlin) but not resistant (5009, high merlin) murine ovarian carcinoma cells. However, stable knockdown of merlin expression in resistant SKOV3-IP and OVCAR10 human ovarian carcinoma cells did not induce sensitivity to FAK inhibition in vitro. These results support the notion that high merlin expression is correlated with a FAK-inhibitor resistant phenotype, likely through an indirect mechanistic linkage. Nevertheless, merlin protein levels may serve as a biomarker to predict ovarian cancer sensitivity or resistance to FAK inhibitor treatment. Supported by NIH CA102310 Citation Format: Nina R. Shah, Isabelle Tancioni, Kristy K. Ward, Christine Lawson, Xiao Lei Chen, Nichol L.G. Miller, Florian J. Sulzmaier, Sean Uryu, David D. Schlaepfer. Low merlin level as a biomarker for sensitivity of ovarian cancer cell lines to FAK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2823. doi:10.1158/1538-7445.AM2014-2823

Objectives: To describe trends in the adoption of robotic surgery for the treatment of uterine malignancy, and the associated impact of these trends on cost of treatment. Methods: University HealthSystem Consortium keeps an administrative database with contributions from over 100 academic medical centers and 250 affiliate hospitals, representing over 90% of US nonprofit academic medical centers. This database was queried to identify all patients with uterine malignancy (ICD-9 182.x, 179) undergoing total hysterectomy (ICD-9 684.x-689) from the 4th quarter of 2008 through the 2nd quarter of 2012. Trends in surgical approach, cost and clinical outcomes were compared by hysterectomy type, including open (OH), robotic (RH) and nonrobotic, minimally invasive (MH). Results: We compared the frequencies of OH, RH and MH in 2009 and 2011, as these were the earliest and most recent full calendar years for which data was available. In 2009 there were 62% OH, 22% RH and 16% MH, while in 2011 there were 54% OH, 32% RH and 14% MH. Since the 4th quarter of 2008, the fraction of RH has increased logarithmically, largely at the expense of OH, which has decreased logarithmically. Thus, we used data from the first two quarters of 2012 to compare current cost and clinical outcomes between OH and RH. Mean direct cost of hospitalization is over $1600 higher for OH as compared to RH. This may be related to the 2.8-fold longer length of stay, 2.4-fold higher complication rate and 2.1-fold higher readmission rate seen with OH as compared to RH. However, despite the increased use of RH over OH, and the reduced cost and complication rate seen with RH over OH, the mean cost of surgical treatment for all patients with uterine malignancy has increased linearly by $521 per year and the overall complication rate has not changed significantly over the period of this study. Conclusions: Although RH is associated with fewer complications and lower cost as compared to OH, and RH use is increasing while the rate of OH declines, we did not find the expected overall decrease in cost and complication rates when the surgical management of all patients with uterine malignancy was evaluated. Complication rates have remained the same and this, along with other factors, may be contributing to the steadily rising cost. A better understanding of the underlying elements associated with complications and cost may help to reduce complications and control costs without compromising quality of care.

6636 Background: The annual cost of 30 day hospital readmissions in the US is $16 billion. The objectives of this study are to determine factors associated with readmission among GO patients, and to create a risk score to identify populations at the highest risk of readmission. Methods: The University HealthSystem Consortium database was queried to identify readmissions among GO patients from 1/1/08 through 9/30/12. Risk factors for 30 day readmission were determined by univariate and multivariate analysis. For each risk factor found to be independently associated with readmission, the low risk group was scored 0 and the high risk group scored 1. The ROR score is the sum of the individual scores. Probability of readmission was calculated for each ROR score. Results: Overall, the readmission rate for GO patients was 4.5%. Vulvar cancer, medical MSDRG, urgent or emergent admission, length of stay > 4 days, and coverage by a public payer (during 1st admission) each was independently associated with readmission. Probability of readmission increases significantly with increasing risk score. Patients with a ROR score of 0 or 1 have a readmission rate of 3.9% (95% CI 3.7% to 4.1%); patients with a ROR score of >1 have a readmission rate of 10.7% (95% CI 10.1% to 11.2%). Conclusions: Specific risk factors and composite risk score are associated with 30 day readmission rate among GO patients. The patient specific ROR score may be used to target transitions of care interventions aimed at reducing readmissions. [Table: see text] [Table: see text]

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that modulates signaling from growth factor, integrin, and cadherin receptors in both tumor and stromal cells. Pharmacological FAK inhibition prevents tumor growth and metastasis, but the target cell action associated with this remains unclear. Recent studies using an inducible endothelial cell (EC) specific FAK kinase-inactive knock-in mouse model revealed that vascular endothelial growth factor (VEGF) increased cell permeability was dependent upon FAK activity. VEGF triggers conformational FAK activation, binding of FAK to the cytoplasmic tail of VE-cadherin, and FAK-dependent phosphorylation of adherens junction proteins regulating vascular integrity. Here we provide genetic and pharmacological support for the importance for FAK activity in mediating direct VE-cadherin tyrosine (Y) 658 phosphorylation in tumor-associated ECs in vivo. In cell culture, VEGF-induced transmigration of tumor cells through an EC barrier is prevented by genetic EC-specific FAK inhibition or reconstitution of Y658F VE-cadherin within null ECs. In mice, VEGF enhances circulating tumor cell extravasation within the lungs and this is prevented by inducible knockin of kinase-dead FAK within ECs. These studies provide a mechanistic foundation for the importance of FAK and VE-cadherin interactions in the regulation of adherens junction stability and support future evaluation of FAK inhibitors in the treatment of metastatic cancer. Citation Format: Chris Jean, Ju-Ock Nam, Xiao-Lei Chen, Sean Uryu, Isabelle Tancioni, Christine Lawson, Kristy K. Ward, Colin T. Walsh, Majid Ghassemian, Patric Turowski, Elisabetta Dejana, Sara M. Weis, David A. Cheresh, David D. Schlaepfer. Inhibiting endothelial FAK activity blocks tumor cell extravasation. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B39.

Objective: Hysterectomy is standard of care in the treatment of endometrial cancer. We will determine if endometrial cancer directed hysterectomy varies by race. Methods: The U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry was queried to identify 59,994 black and white women diagnosed with localized endometrial cancer from 2000-2009. Frequency of endometrial cancer directed hysterectomy was compared by race (white, black) and adjusted for age ( Results: Of the 59,994 women with localized endometrial malignancies in the study, 55,950 were white and 4,044 were black. White females with localized endometrial cancer were significantly more likely to undergo hysterectomy than their black counterparts (95.69% [94.88-96.5%] vs. 86.55% [86.55-92.4%]). Black women 60 and older were significantly less likely to receive hysterectomy than their white counterparts (87.50% vs. 94.96%). In accounting for grade, white women with low grade endometrial cancer were significantly more likely to undergo hysterectomy than black women (96.23% vs. 91.37%). There was no significant difference in hysterectomy in women less than age 60 or among those with high-grade disease. When reason for no hysterectomy was queried, it was found that reason “not recommended” was significantly higher for black women than white women (50.82% [44.28-58.05%] vs. 40.28% [37.79-42.90%]). Furthermore, when accounting for age and grade, black women were still more likely to have no surgery because it was not recommended, but the only statistically significant racial disparity was in women less than 60 years old (41.57% [38.26-44.97%] vs. 54.41% [46.02-62.56%]). Five-year survival for all women with hysterectomy was 98.8% (95% CI = 98.4-99.1%). White subjects that underwent hysterectomy had a significantly higher 5-year survival than black subjects (99.2% [98.7-99.5%] vs. 92.6% [90.6-94.1%]). The significant racial difference in 5-year survival persisted when accounting for age and grade. Conclusions: We found substantial racial disparities between black and white women with localized endometrial cancer in the frequency of hysterectomy performed and in 5-year survival. This, as yet, unexplained racial disparity merits further study to identify causative factors to ultimately improve health care outcomes for all women with endometrial cancer. Citation Format: Travis-Riley K. Korenaga, Kristy K. Ward, Michael T. McHale, Cheryl C. Saenz, Steven C. Plaxe. Racial disparities in surgical procedure and survival for endometrial cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B59.

Purpose: To evaluate the association of county level characteristics with the incidence of invasive squamous cell carcinoma of the cervix among Hispanic women. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program's 18 registries from 2000-2009 were queried and average annual age-adjusted incidence rates per 100,000 Hispanic women for invasive squamous cell carcinoma of the cervix (SCC) were calculated. Patients were stratified by residence in a county with high versus low percent language isolation, percent of Hispanics with less than a high school education and percent of Hispanic families below the poverty level. Results: Between 2000-2009, 5,534 Hispanic women were diagnosed with SCC in SEER. Incidence rates were highest among those living in counties with high levels of LI (8.9 v 10.7), or low levels of education (8.9 v 10.8) or income (8.7 v 11.0). The incidence of SCC was significantly less in women living in counties with higher levels of education and income and lower levels of LI than among those living in counties with lower levels of education and income and higher levels of LI (8.6 v. 11.3). Counties that have higher levels of income and education are less likely to be LI whereas counties with lower levels of income and education are more likely to be LI. Conclusions: Among Hispanic women, county level characteristics such as LI, education, and income have a complex interaction that appears to be associated with the incidence of SCC. Community level interventions need to be evaluated to decrease the high incidence of SCC in this population. Citation Format: Kristy K. Ward, Angelica M. Roncancio, Steven C. Plaxe. The association of county level characteristics with the incidence of squamous cell carcinoma of the cervix in Hispanic women. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A54.

Background: The Agency for Healthcare Research and Quality of the US Department of Health and Human Services notes that healthcare quality problems are reflected in a wide variation in the use of health care services. Endometrial cancer is the most common gynecologic malignancy in the United States. Incidence varies with age and race/ethnicity and is most common among post-menopausal and White women. Describing regional variations in incidence rates can help to address disparities through better understanding and may also facilitate allocation of healthcare resources. Methods: The NCI's Surveillance, Epidemiology, and End Results (SEER) dataset was queried to identify all 92,857 women diagnosed with endometrial cancer from 2000-2009 in the 16 geographically determined registries included in this study. Average annual age-adjusted incidence rates (per 100,000 women) were calculated and adjusted for race/ethnicity, and age < or ≥ to 60 years and compared between the regional registries. The “Non-Hispanic White” population was compared to “Other” including women of all other races/ethnicities, which were combined since the incidence of endometrial cancer was similar for black, Hispanic, and women of other races/ethnicities. Results: For women of all ages combined, there was no significant difference in incidence between Non-Hispanic Whites and Others in the Hawaii registry; in all other registries, the incidence in Non-Hispanic White women significantly exceeded the incidence in Others. The greatest disparity was seen in Iowa, where the incidence in Non-Hispanic Whites was 14.4/100,000 cases higher. The least disparity was seen in Louisiana (1.7/100,000 excess cases). Among women < 60 at diagnosis, Hawaii is the lone registry in which women of other race/ethnicity have a higher incidence than Non-Hispanic White women. The greatest disparity in women less than 60 was in Iowa (7.3/100,000 excess cases) and the smallest significant disparity was in the California (excluding SJ/LA/SF) registry (1.4/100,000 excess cases). For women 60 or older at diagnosis, only in the Greater Georgia and Louisiana registries did the incidence in Others exceed the incidence in Non-Hispanic Whites. Of the 14 remaining registries, 13 had significantly higher incidence in Non-Hispanic White women. The greatest disparity was in Iowa, where incidence in Non-Hispanic Whites was 50.4/100,000 cases higher. The least disparity in women diagnosed 60 or older was in the Atlanta registry (9.5/100,000 excess cases). The only registry with no incidence disparity in women 60 and older was Kentucky. Conclusions: We found geographic location greatly modifies racial and ethnic disparities in the incidence of endometrial cancer, regardless of age. This, as yet, unexplained variation in racial/ethnic disparity based on geography merits further study to identify causative factors as well as to help guide rational allocation of healthcare resources. Citation Format: Travis-Riley K. Korenaga, Kristy K. Ward, Michael T. McHale, Cheryl C. Saenz, Steven C. Plaxe. Place of residence modifies racial/ethnic disparities in the incidence of endometrial cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A55.

Objective To determine whether the level of cultural adaptation (acculturation) of Hispanic women is associated with increased sexual risk behaviors and cervical cytological abnormalities. Study Design Hispanic women 18-55 years of age (mean, 30.5 ± 8.32 years) underwent routine Papanicoulaou testing and completed a comprehensive survey (n = 3149). Acculturation (cultural adaptation) was measured using the Short Acculturation Scale for Hispanics. Structural equation modeling was used to test a mediation model. Results Highly acculturated women engaged in a greater number of sexual risk behaviors and were more likely to have an abnormal Papanicoulaou test when compared to less acculturated Hispanic women ( P Conclusion Acculturation is related to sexual risk taking and abnormal cervical cytology. Determination of acculturation level as part of culturally competent health care will aid in tailoring patient communication and counseling on the prevention of cervical cancer among Hispanic women.